The current paradigm of T cell function in the immune response is that T cells recognize antigen through the T cell antigen receptor (TCR) which transduces signals to the cytoplasm by way of cytosolic priming and effector tyrosine kinases. The TCR acts in a monovalent fashion is crosslinked by its antigen/MHC (pMHC) ligand, causing TCR triggering. However, our more recent data indicate that the TCR is organized in pre-existing oligomers, and therefore it might not require crosslinking, and that the triggered TCR adopts, upon ligand binding, an active conformation that is responsible for recruiting cytoplasmic effector molecules. We have found novel direct effectors of the TCR, including the Ras GTPase TC21 and unveiled that these effectors play an essential role in a variety of TCR signaling functions including tonic signaling and TCR downregulation. Furthermore, we have found that TC21 is required for the acquisition of pMHC by T cells from the APCs and re-express it on their own plasma membrane, becoming themselves APCs for other T cells. In this proposal we wish to explore several of the avenues open by our most recent findings, including the importance of pMHC presentation by T cells. Another objective is to study an interesting property of the conformational change in the TCR: its return to the inactive conformation even when it is still bound to its pMHC ligand (countdown effect). We also propose to use approaches that alter the size of pre-existing TCR oligomers to seek for new ways of modulating T cell activation. The last two objectives refer to study the role of TC21 as a direct effector of the B cell antigen receptor (BCR). We propose to study the involvement of TC21 in the B cell germinal center response and how the deregulation of its expression can influence the transformation of GC B cells into lymphomas. Finally, we propose to generate small molecular weight inhibitors of TC21 as potential drugs for the treatment of lymphomas.
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